EP1968598B1 - Pyrimidin-2,4-diamine und ihre anwendungen - Google Patents

Pyrimidin-2,4-diamine und ihre anwendungen Download PDF

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EP1968598B1
EP1968598B1 EP06851988.3A EP06851988A EP1968598B1 EP 1968598 B1 EP1968598 B1 EP 1968598B1 EP 06851988 A EP06851988 A EP 06851988A EP 1968598 B1 EP1968598 B1 EP 1968598B1
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group
aryl
compound
heteroaryl
alkyl
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EP1968598A4 (de
EP1968598A1 (de
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Somasekhar Bhamidipati
Rajinder Singh
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Rigel Pharmaceuticals Inc
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Rigel Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E10/00—Energy generation through renewable energy sources
    • Y02E10/50—Photovoltaic [PV] energy
    • Y02E10/549—Organic PV cells

Definitions

  • the invention relates to compounds containing the pyrimidine-2,4-diamine moiety, particularly diaryl pyrimidine-2,4-diamines, compositions comprising the compounds, and methods of using the compounds and compositions for the inhibition of kinases.
  • the compounds and compositions are useful for treating or modulating disease in which kinases may be involved, symptoms of such disease, or the effect of other physiological events mediated by kinases.
  • the protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell. ( Hardie and Hanks (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif .). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Protein kinases catalyze phosphorylation of the hydroxyl moiety of serine, threonine or tyrosine.
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.), and sequence motifs generally corresponding to each of the kinase families have been identified.
  • the phosphorylation and dephosphorylation is an important post-translational control element in eukaryotic signal transduction.
  • the phosphorylation state of a given protein can govern its enzyme activity, protein-protein binding interactions, and cellular distribution.
  • protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function.
  • a partial list of such kinases includes abl, AKT, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSFir, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ron, Syk, Src, tie, tie2, TRK, Yes, and Zap70. Inhibition of the kinases has become an important therapeutic target.
  • Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc.
  • the appropriate protein kinase functions in signaling pathways to activate or inactivate, for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
  • Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
  • the Src family is composed of ten highly homologous cytosolic kinases which are critical components in an array of cell signaling pathways ranging from lymphocyte activation to cell growth and proliferation. Constitutive activation of these enzymes can lead to oncogenic cell transformation, making them putative drug targets for cancer therapies. Because of their importance in the regulation of these fundamental cellular processes, many studies have focused on developing inhibitors for the Src family kinase. However, the potent inhibitors that have been discovered lack the high selectivity that would be required for probing the cellular inhibition of an individual target kinase. Conventional inhibitor screens have produced few if any molecules which can discriminate between the active sites of the various Src family kinases.
  • WO01/00213 describes substituted pyrimidines as Src kinase inhibitors.
  • WO01/40218 describes arylamine derivatives for use as anti-telomerase agents.
  • WO00/39101 describes substituted pyrimidines as anti-cancer agents.
  • WO01/29009 describes substituted pyrimidines as kinase inhibitors, while WO00/39101 , WO00/59892 , and WO01/47921 describe amino substituted pyrimidines as kinase inhibitors.
  • U.S. Pat. No. 6,080,858 describes a process for preparing substituted pyrimidines.
  • WO01/19825 describes amino substituted pyrimidines as synthetic intermediates.
  • WO01/72745 describes 4-heteroaryl-substituted pyrimidines as inhibitors of CDK's.
  • WO01/72717 describes 4-amino-5-cyanopyrimidines as inhibitors of CDK's.
  • WO02/22601 describes 4-(pyrazol-5-ylamino)-pyrimidines as kinase inhibitors.
  • WO02/46184 describes 4-(4-pyrazolyl)-pyrimidines as kinase inhibitors.
  • WO02/46170 and WO02/46171 describes 2-anilino-pyrimidines as inhibitors of JNK and IKK, respectively.
  • WO02/47690 describes 4-arylamino-pyrimidines as kinase inhibitors.
  • 2,4-pyrimidinediamine compounds are also potent inhibitors of the tyrosine kinase Syk kinase.
  • Examples of such 2,4-pyrimidinediamine are described, for example, in U.S. application Serial No. 10/355,543 filed January 31,2003 ( US2004/0029902A1 ), international application Serial No. PCT/US03/03022 filed January 31,2003 ( WO 03/063794 ), U.S. application Serial No. 10/631,029 filed July 29, 2003 , international application Serial No. PCT/US03/24087 ( WO2004/014382 ), U.S. application Serial No. 10/903,263 filed July 30, 2004 ( US2005/0234049 ), and international application Serial No. PCT/US2004/24716 ( WO2005/016893 ).
  • the present invention provides pyrimidine-2,4-diamine compounds, which may be used, e.g. in the form of compositions and in vitro methods of using the compounds to inhibit kinases.
  • the progroup generally includes a group or moiety that is metabolized under the conditions of use to yield the active pyrimidine-2,4-diamine drug, and is covalently attached to the drug via a carbamate, a thiocarbamate, a dithiocarbamate, a urea, or a thiourea linkage.
  • Virtually any known pyrimidine-2,4-diamine compound that has biological, and hence therapeutic, activity can be protected at an available primary or secondary amine of the parent drug molecule with one or more progroups which include a group or moiety which is metabolized under conditions of use to yield the active pyrimidine-2,4,diamine drug, and is covalently attached to the drug via a carbomate, a thiocarbomate, a dithiocarbamate, a urea, or a thiourea linkage.
  • Suitable active pyrimidine-2,4-diamine compounds are described, for example, in U.S. application Serial No.10/355,543 filed January 31, 200 ( US2004/0029902A1 ), international application Serial No.
  • PCT/US03/03022 filed January 31, 2003 ( WO 03/063794 ), U.S. application Serial No. 10/631,029 filed July 29, 2003 , international application Serial No. PCT/US03/24087 ( WO2004/014382 ), U.S. application Serial No. 10/903,263 filed July 30 , ( US2005/0234049 ), and international application Serial No. PCT/US2004/24716 ( WO2005/016893 ).
  • the progroup(s) can be attached to any available primary or secondary amine, including, for example, the N2 nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the pyrimidine-2,4-diamine moiety, and/or a primary or secondary nitrogen atom included in a substituent on the pyrimidine-2,4-diamine compound.
  • the compounds of the invention are potent inhibitors of kinases. Accordingly, in still another aspect, the present invention provides in vitro methods of inhibiting kinases comprising contacting a kinase with an effective amount of a compound or composition of the invention effective for inhibition.
  • the compounds of the invention can be for use in the treatment of neoplasia including cancer and metastasis.
  • the compounds of the invention are also useful in promoting apoptosis, and in the treatment and prevention of other diseases associated with protein kinases.
  • Compounds of the present invention are useful for, but not limited to, the prevention or treatment of cancer and related diseases.
  • the compounds of the invention have kinase inhibitory activity, therefore, the compounds of the invention can be useful in therapy as antineoplasia agents.
  • Compounds of the invention can be useful for the treatment of carcinomas, hematopoietic tumors, solid tumors, sarcomas, retinoblastoma, hematopoietic malignancies, including leukemias and lymphomas, tumor-induced pleural or pericardial effusions, and are also useful for promoting apoptosis.
  • the compounds of this invention can act as inhibitors of protein kinases, such as Syk, Src, ErbB, KDR, CDK-2, LCK, CDK-5, IKK, JNK3, and thus be effective in the treatment of diseases associated with these protein kinases.
  • protein kinases such as Syk, Src, ErbB, KDR, CDK-2, LCK, CDK-5, IKK, JNK3, and thus be effective in the treatment of diseases associated with these protein kinases.
  • the present invention provides compounds containing the pyrimidine-2,4-diamine moiety, particularly diaryl pyrimidine-2,4-diamine moiety, and compositions comprising the compounds.
  • the compounds have the general structure shown below: where X and Y are independently selected from oxygen, amino or substituted amino, S(O) 0-2 , or substituted or unsubstituted carbon; R', R", and R"' are optional substituents; and R"" is H or a progroup, R P .
  • the progroup R P is covalently attached via a carbamate, a thiocarbamate, a dithiocarbamate, a urea, or a thiourea linkage to any one or more of the 2'-N, the 4'-N, or to X or Y when they are amino.
  • the compounds and compositions can be used in methods for the inhibition of kinases.
  • the compounds of the invention have the formula (I): wherein R 3 is aryl or heteroaryl that is optionally substituted; X 3 and X 4 are independently selected from CH or N; X 5 is selected from the group consisting of CR 12 R 13 , O, S, SO, SO 2 , and NR 14 , wherein R 12 and R 1 are independently selected from H, OH, or lower alkyl; R 4 is an electronegative group; R', R 5 , R 6 and R 14 are independently selected from H, lower alkyl, a progroup, cycloalkyl or aryl, and wherein at least one of R', R 5 , R 6 or R 14 is the aforementioned progroup linked via a constitutent carbamate, a thiocarbamate, a dithiocarbamate, a urea, or a thiourea linkage; R 7 and R 8 are independently selected from the group consisting of H, halogen, lower alkyl, cycloalkyl
  • the present invention provides compounds of formula (II):
  • the compounds may be for use in methods of treating and/or preventing cancer.
  • the compounds may be for use in methods which generally involve administering to a subject that has cancer or that is at risk of developing cancer an amount of a compound or composition of the invention effective to treat or prevent the disease.
  • the compounds may be for use in a method which may be practiced in animals or in humans
  • 2,4-pyrimidinediamine compounds are also potent inhibitors of the tyrosine kinase Syk kinase. Examples of such 2,4-pyrimidinediamine compounds are described, for example, in U.S. application Serial No. 10/355,543 filed January 31, 2003 ( US2004/0029902A1 ), international application Serial No. PCT/US03/03022 filed January 31, 2003 ( WO 03/063794 ), U.S. application Serial No. 10/631,029 filed July 29,2003, international application Serial No. PCT / US03/24087 ( WO2004/014382 U.S. application Serial No. 10/903,263 filed July 30, 2004 ( US2005/0234049 ), and international application Serial No.
  • the present disclosure provides in vitro methods of inhibiting, Syk kinase activity which method involves contacting a Syk kinase with an amount of a compound of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to inhibit Syk kinase activity.
  • the Syk kinase is an isolated or recombinant Syk kinase.
  • the Syk kinase is an endogenous or recombinant Syk kinase expressed by a cell, for example a mast cell or a basophil cell.
  • the method is practiced in in vitro wherein the contacting is performed under conditions in which the progroup(s) metabolize to yield the active 2,4-pyrimidinediamine compound.
  • the method generally involves contacting a Syk-dependent receptor or a cell expressing a Syk-dependent receptor with an amount of a suitable compound of the invention described herein, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit the signal transduction cascade.
  • the methods can also be used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular Syk-dependent signal transduction cascade.
  • the methods can be practiced to regulate any signal transduction cascade involving Syk.
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used.
  • An alkyl group comprises from 1 to 15 carbon atoms (C 1 -C 15 alkyl), preferably from 1 to 10 carbon atoms (C 1 -C 10 alkyl) and more preferably from 1 to 6 carbon atoms (C 1 -C 6 alkyl or lower alkyl).
  • Alkanyl by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl; pentanyls, such as pent-1-yl, pent-2-yl, pent-3-yl, cyclopent-1-yl; hexanyls, such as hexan-1-yl, hex
  • Alkenyl by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl , prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl , but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc. ; and the like.
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc. ; and the like.
  • Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
  • Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,2-d
  • alkyldiyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyldiyl).
  • saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenos, defined infra ).
  • Alkoxy by itself or as part of another substituent, refers to a radical of the formula -OR, where R is an alkyl or cycloalkyl group as defined herein.
  • Representative examples alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • Alkoxycarbonyl by itself or as part of another substituent, refers to a radical of the formula -C(O)-alkoxy, where alkoxy is as defined herein.
  • Alkylthio by itself or as part of another substituent, refers to a radical of the formula -SR, where R is an alkyl or cycloalkyl group as defined herein.
  • Representative examples of Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Aryl by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,
  • An aryl group comprises from 6 to 20 carbon atoms (C 6 -C 20 aryl), preferably from 6 to 15 carbon atoms (C 6 -C 15 aryl) and more preferably from 6 to 10 carbon atoms (C 6 -C 10 aryl).
  • Arylalkyl by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group as, as defined herein.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • an arylalkyl group is (C 6 -C 30 ) arylalkyl, e.g ., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) alkyl and the aryl moiety is (C 6 -C 20 ) aryl, more preferably, an arylalkyl group is (C 6 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 8 ) alkyl and the aryl moiety is (C 6 -C 12 ) aryl, and even more preferably, an arylalkyl group is (C 6 -C 30 ) arylalkyl, e.g ., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group
  • Aryloxy by itself or as part of another substituent, refers to a radical of the formula -O-aryl, where aryl is as defined herein.
  • Arylalkyloxy by itself or as part of another substituent, refers to a radical of the formula -O-arylalkyl, where arylalkyl is as defined herein.
  • Aryloxycarbonyl by itself or as part of another substituent, refers to a radical of the formula -C(O)-O-aryl, where aryl is as defined herein.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the barrier to rotation is high enough to allow for the isolation of the conformers ( Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994; Chapter 14 ). Atropisomerism is significant because it introduces an element of chirality in the absence of stereogenic atoms. The invention is meant to encompass atropisomers.
  • Carbamoyl by itself or as part of another substituent, refers to a radical of the formula -C(O)NR'R", where R' and R" are each, independently of one another, selected from the group consisting of hydrogen, alkyl and cycloalkyl as defined herein, or alternatively, R' and R", taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered cycloheteroalkyl ring as defined herein, which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, S and N.
  • Compounds of the invention refers to compounds encompassed by the various descriptions and structural formulae disclosed herein.
  • the compounds of the invention may be identified by either their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and therefore may exist as stereoisomers, such as double-bond isomers ( i.e. , geometric isomers), rotamers, enantiomers or diastereomers. Accordingly, when stereochemistry at chiral centers is not specified, the chemical structures depicted herein encompass all possible configurations at those chiral centers including the stereoisomerically pure form (e.g.
  • the compounds of the invention may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds of the invention may also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes examples include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the hydrated, solvated and N-oxide forms are within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Cycloalkyl by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined herein. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used.
  • Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
  • the cycloalkyl group comprises from 3 to 10 ring atoms (C 3 -C 10 cycloalkyl) and more preferably from 3 to 7 ring atoms (C 3 -C 7 cycloalkyl).
  • Cycloheteroalkyl by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
  • Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like.
  • the cycloheteroalkyl group comprises from 3 to 10 ring atoms (3-10 membered cycloheteroalkyl) and more preferably from 5 to 7 ring atoms (5-7 membered cycloheteroalkyl).
  • a cycloheteroalkyl group may be substituted at a heteroatom, for example, a nitrogen atom, with a lower alkyl group.
  • a heteroatom for example, a nitrogen atom
  • N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included within the definition, of "cycloheteroalkyl.”
  • a cycloheteralkyl group may be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom.
  • Dialkylamino or " Monoalkylamino ,” by themselves or as part of other substituents, refer to radicals of the formula -NRR and -NHR, respectively, where each R is independently selected from the group consisting of alkyl and cycloalkyl, as defined herein.
  • Representative examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like.
  • Representative examples of monalkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, cyclohexylamino, and the like.
  • Electronegative by itself or as part of another substituent, refers to the tendency of a substituent to attract valence electrons from neighboring atoms.
  • Exemplary electron-withdrawing groups include, acyl, formyl, sulfonyl, alkoxy, carboxylate, haloalkyl, chloride, fluoride, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, MeO, and the like
  • Halogen or " Halo ,” by themselves or as part of another substituent, refer to a fluoro, chloro, bromo and/or iodo radical.
  • Haloalkyl by itself or as part of another substituent, refers to an alkyl group as defined herein in which one or more of the hydrogen atoms is replaced with a halo group.
  • haloalkyl is specifically meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc . up to perhaloalkyls.
  • the halo groups substituting a haloalkyl can be the same, or they can be different.
  • (C 1 -C 2 ) haloalkyl includes 1-fluoromethyl, 1-fluoro-2-chloroethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1, 1-difluoroethyl, 1, 2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc .
  • Haloalkyloxy by itself or as part of another substituent, refers to a group of the formula -O-haloalkyl, where haloalkyl is as defined herein.
  • Heteroalkyl refers to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups.
  • Typical heteroatoms or heteroatomic groups which can replace the carbon atoms include, but are not limited to, O, S, N, Si, -NH-, -S(O)-, -S(O) 2 -, -S(O)NH-, -S(O) 2 NH- and the like and combinations thereof.
  • the heteroatoms or heteroatomic groups may be placed at any interior position of the alkyl, alkenyl or alkynyl groups.
  • the heteratom or heteratomic group can also occupy either or both chain termini. For such groups, no orientation of the group is implied.
  • Heteroaryl by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring systems, as defined herein.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, ß-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
  • the heteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl), preferably from 5 to 10 ring atoms (5-10 membered heteroaryl).
  • Preferred heteroaryl groups are those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.
  • Heteroarylalkyl by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used.
  • the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g ., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl moiety is a 5-15-membered heteroaryl.
  • the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g ., the alkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.
  • Parent Aromatic Ring System refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system. Specifically included within the definition of "parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc .
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as -indacene, s -indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc .
  • Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thi
  • Pharmaceutically acceptable salt refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesul
  • salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see , e.g ., Berge et al., 1977, J. Pharm. Sci. 66:1-19 ).
  • Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY .
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ”), tert -butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (e.g ., methyl and ethyl esters, acetate or propionate groups or glycol esters) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
  • acylated e.g ., methyl and ethyl esters, acetate or propionate groups or glycol esters
  • alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
  • Prodrug refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug.
  • Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
  • Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety or "progroup” which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug.
  • the cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, or combination thereof.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
  • progroups suitable for masking functional groups in active compounds to yield prodrugs are well-known in the art.
  • a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vitro to provide the hydroxyl group.
  • An amino functional group may be masked as an amide, imine, phosphinyl, phosphonyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group.
  • a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group.
  • ester including silyl esters and thioesters
  • amide or hydrazide promoiety which may be hydrolyzed in vivo to provide the carboxyl group.
  • suitable progroups and their respective promoieties will be apparent to those of skill in the art.
  • Progroup refers to a type of protecting group that, when used to mask a functional group within an active drug, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use.
  • Substituted when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s).
  • substituent groups for substituting unsaturated carbon atoms in the specified group or radical are -R a , halo, -O - , -OR b , -SRV, -S - , -NR c R c , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -S(O) 2 R b , -S(O) 2 O - , -S(O) 2 OR b , -OS(O) 2 R b , -OS(O) 2 O - , -OS(O) 2 OR b , -P(O)(O - ) 2 , -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b ,
  • Substituent groups for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups are -R a , -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R b , -S(O) 2 O - , -S(O) 2 OR b , -OS(O) 2 R b , -OS(O) 2 O - , -OS(O) 2 OR b , -P(O)(O - ) 2 , -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )
  • Syk Kinase refers to the well-known 72 kDa non-receptor (cytoplasmic) spleen protein tyrosine kinase expressed in B-cells and other hematopoetic cells. Syk kinase includes two consensus Src-homology 2 (SH2) domains in tandem that bind to phosphorylated immunoreceptor tyrosine-based activation motifs ("ITAMs”), a "linker” domain and a catalytic domain (for a review of the structure and function of Syk kinase see Sada et al., 2001, J. Biochem.
  • SH2 consensus Src-homology 2
  • Syk kinase has been extensively studied as an effector of B-cell receptor (BCR) signaling (Turner et al ., 2000, supra ). Syk kinase is also critical for tyrosine phosphorylation of multiple proteins which regulate important pathways leading from immunoreceptors, such as Ca 2+ mobilization and mitogen-activated protein kinase (MAPK) cascades and degranulation. Syk kinase also plays a critical role in integrin signaling in neutrophils ( see , e.g ., Mocsai et al. 2002, Immunity 16:547-558 ).
  • Syk kinase includes kinases from any species of animal, including but not limited to, homosapiens, simian, bovine, porcine, rodent, etc., recognized as belonging to the Syk family. Specifically included are isoforms, splice variants, allelic variants, mutants, both naturally occurring and man-made. The amino acid sequences of such Syk kinases are well known and available from GENBANK. Specific examples of mRNAs encoding different isoforms of human Syk kinase can be found at GENBANK accession no.
  • the term "subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish.and the like. The term does not denote a particular age or gender.
  • the terms “treat” or “treatment” are used interchangeably and are meant to indicate a postponement of development of a disease and/or a reduction in the severity of such symptoms that will or are expected to develop, where the disease is associated with the functioning of a kinase.
  • the terms further include ameliorating existing symptoms, preventing additional symptoms, and ameliorating or preventing the underlying metabolic causes of symptoms.
  • the compounds of the present invention may be used to inhibit or reduce the activity ofkinases.
  • inhibition and reduction of activity of kinases refers to a lower level of the measured activity relative to a control experiment in which the cells or the subjects are not treated with the test compound.
  • the inhibition or reduction in the measured activity is at least a 10% reduction or inhibition.
  • reduction or inhibition of the measured activity of at least 20%, 50%, 75%, 90% or 100%, or any number in between, may be preferred for particular applications.
  • the instant disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, as defined in formula (II).
  • Various 2,4-pyrimidinediamine compounds are described in U.S. application Serial No. 10/355,543 filed January 31, 2003 ( US2004/0029902A1 ), international application Serial No. PCT/US03/03022 filed January 31, 2003 ( WO 03/063794 ), U.S. application Serial No. 10/631,029 filed July 29, 2003 , international application Serial No. PCT/US03/24087 ( WO2004/014382 ), U.S. application Serial No. 10/903,263 filed July 30, 2004 ( US2005/0234049 ), and international application Serial No.
  • Prodrugs of pyrimidine-2,4-diamine compounds as defined in formula (II) are of particular interest, as these compounds inhibit kinases, such as inhibiting upstream Fc receptor signaling cascades well as Syk kinase and Syk kinase-dependent signaling cascades.
  • the nature of the progroup can vary, and will depend upon, among other factors, the desired water solubility of the prodrug, its intended mode of administration and/or its intended mechanism or site of metabolism to the active 2,4-pyrimidinediamine compound.
  • the identity of the R 3 group can also be selected so as to impart the prodrug with desirable characteristics.
  • lipophilic groups can be used to decrease water solubility and hydrophilic groups can be used to increase water solubility. In this way, prodrugs specifically tailored for selected modes of administration can be obtained.
  • the R 3 group can also be designed to impart the prodrug with other properties, such as, for example, improved passive intestinal absorption, improved transport-mediated intestinal absorption, protection against fast metabolism (slow-release prodrugs), tissue-selective delivery, passive enrichment in target tissues, targeting-specific transporters, etc.
  • R 3 groups capable of imparting prodrugs with these characteristics are well-known, and are described, for example, in Ettmayer et al. (2004) J. Med. Chem. 47: 2393-2404 . All of the various R 3 groups described in these references can be utilized in the prodrugs described herein.
  • any particular progroup for a desired mode of administration can be confirmed in biochemical assays.
  • a prodrug is to be administered by injection into a particular tissue or organ, and the identities of the various enzyme(s) expressed in the tissue or organ are known
  • the particular prodrug can be tested for metabolism in biochemical assays with the isolated enzyme(s).
  • the particular prodrug can be tested for metabolism to the active 2,4-pyrimidinediamine compound with tissue and/or organ extracts.
  • tissue and/or organ extracts can be of particular convenience when the identity(ies) of the enzymes expressed in the target tissues or organs are unknown, or in instances when the isolated enzymes are not conveniently available. Skilled artisans will be able to readily select progroups having metabolic properties (such as kinetics) suitable for particular applications using such in vitro tests.
  • the specific prodrugs could also be tested for suitable metabolism in in vitro animal models.
  • the present invention provides compounds of formula (II)
  • the present invention provides compounds of formula (III): wherein X 1 is O or NR 11 ; R is selected from the group consisting of straight or branched, saturated or unsaturated alkyl, allyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl; and n is and integer between 0 and 10.
  • R can be morpholine,1- methylpiperidine, piperazine, 4-(3-propane-1-sulfonic acid) piperazin-1-yl, dimethylamino, tryptamine, N-tert-butylaceyltryptamine, phosphate, methyl phosphate, dimethyl phosphate, phosphonate, and the like.
  • Exemplary prodrugs are described in Examples 1-10 and in Figure 1 .
  • a carbamoyl chloride is produced which is then used to make prodrugs of the invention.
  • haloalkyl carbamate intermediates for example but not limited to intermediate 10 where the carbamate is on the N2-nitrogen, can be made at various positions on the 2,4-pyrimidinediamine and further converted into prodrugs of the invention.
  • chloromethyl ether carbamates can be reacted with imines, like pyridine, to make pyridinium salt prodrugs, 11.
  • chloromethyl ether carbamates can be reacted with alcohols or alkoxides to make acetal-carbamate prodrugs, 12.
  • chloromethyl ether carbamates can be reacted with silver phosphonate salts to make mixed phosphate-acetal-carbamate prodrugs, 13.
  • chloromethyl ether carbamates can be reacted with carboxylate salts to make ester-acetal-carbamate prodrugs, 14.
  • the compounds of the invention described herein may include functional groups that can be masked with progroups to create prodrugs.
  • prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form.
  • progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art.
  • the compounds of the invention comprise isoxazoloanthrones, as described above.
  • the compounds can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or Maybridge (Cornwall, England), or the compounds can be synthesized.
  • the compounds of the present invention, and other related compounds having different subtituents identified by any of the methods described above can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992 ); Carey and Sundberg, ADVANCED ORGANIC CHEMISTY 3rd Ed., Vols.
  • the compounds and intermediates described herein can be synthesized via a variety of different synthetic routes using commercially, available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely used and/or adapted to synthesize active 2,4-pyrimidinediamine compounds can be found in U.S. Patent No. 5,958,935 , U.S. application Serial No. 10/355,543 filed January 31, 2003 ( US2004/0029902A1 ), international application Serial No. PCT/US03/03022 filed January 31, 2003 ( WO 03/063794 ), U.S. application Serial No. 10/631,029 filed July 29, 2003 , international application Serial No.
  • the procedures described herein for synthesizing the compounds of the invention may include one or more steps of protection and deprotection (e.g., the formation and removal of acetal groups).
  • the synthetic procedures disclosed below can include various purifications, such as column chromatography, flash chromatography, thin-layer chromatography (TLC), recrystallization, distillation, high-pressure liquid chromatography (HPLC) and the like.
  • various techniques well known in the chemical arts for the identification and quantification of chemical reaction products such as proton and carbon-13 nuclear magnetic resonance ( 1 H and 13 C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, elemental analysis (EA), HPLC and mass spectroscopy (MS) can be used as well.
  • Methods of protection and deprotection, purification and identification and quantification are well known in the chemical arts.
  • Compounds of the present invention are useful for, but not limited to, the prevention or treatment of cancer and related diseases.
  • the compounds of the invention have kinase inhibitory activity, such as Syk kinase inhibitory activity, Src kinase inhibitory activity, IGF-1R inhibitory activity, and the like.
  • the compounds of the invention are useful in therapy as antineoplasia agents.
  • neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of me
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
  • the compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • cancer related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.
  • the compounds of the present invention can also be useful for promoting apoptosis.
  • the compounds of this invention can also act as inhibitors of other protein kinases, e.g. ErbB, KDR, CDK-2, LCK, CDK-5, IKK, JNK3, and thus be effective in the treatment of diseases associated with other protein kinases.
  • other protein kinases e.g. ErbB, KDR, CDK-2, LCK, CDK-5, IKK, JNK3, and thus be effective in the treatment of diseases associated with other protein kinases.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the compounds of the present invention include the pharmaceutically acceptable derivatives thereof.
  • the compounds of the invention and/or compositions thereof are useful in the treatment and/or prevention diseases in animals and humans caused by kinases.
  • the compounds may be for administration per se , but are typically formulated for administration in the form of a pharmaceutical composition.
  • the exact composition will depend upon, among other things, the method of administration and will apparent to those of skill in the art. A wide variety of suitable pharmaceutical compositions are described, for example, in Remington's Pharmaceutical Sciences, 20th ed., 2001 ).
  • compositions may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the active compound suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.
  • liquid solutions such as an effective amount of the active compound suspended in diluents, such as water, saline or PEG 400
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin
  • suspensions in an appropriate liquid such as water, saline or PEG 400
  • Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, com starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • a flavor e.g., sucrose
  • an inert base such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.
  • Aerosol formulations i.e., they can be "nebulized" to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged nucleic acid with a suppository base.
  • Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the compound of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally.
  • a specific example of a suitable solution formulation may comprise from about 0.5-100 mg/ml compound and about 1000 mg/ml propylene glycol in water.
  • Another specific example of a suitable solution formulation may comprise from about 0.5-100 mg/ml compound and from about 800-1000 mg/ml polyethylene glycol 400 (PEG 400) in water.
  • a specific example of a suitable suspension formulation may include from about 0.5-30 mg/ml compound and one or more excipents selected from the group consisting of: about 200 mg/ml ethanol, about 1000 mg/ml vegetable oil (e.g., corn oil), about 600-1000 mg/ml fruit juice (e.g., grapefruit juice), about 400-860 mg/ml milk, about 0.1 mg/ml carboxymethylcellulose (or microcrystalline cellulose), about 0.5 mg/ml benzyl alcohol (or a combination of benzyl alcohol and benzalkonium chloride) and about 40-50 mM buffer, pH 7 (e.g., phosphate buffer, acetate buffer or citrate buffer or, alternatively 5% dextrose may be used in place of the buffer) in water.
  • excipents selected from the group consisting of: about 200 mg/ml ethanol, about 1000 mg/ml vegetable oil (e.g., corn oil), about 600-1000 mg/ml fruit juice (e.g., grapefruit juice
  • a specific example of a suitable liposome suspension formulation may comprise from about 0.5-30 mg/ml compound, about 100-200 mg/ml lecithin (or other phospholipid or mixture of phospholipids) and optionally about 5 mg/ml cholesterol in water.
  • formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.
  • Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the composition can, if desired, also contain other compatible therapeutic agents, discussed in more detail, below.
  • the compounds of the invention are for administration to patients at dosage levels suitable to achieve therapeutic benefit.
  • therapeutic benefit is meant that the administration of compound leads to a beneficial effect in the patient over time.
  • Initial dosages suitable for administration to humans may be determined from in vitro assays or animal models.
  • an initial dosage may be formulated to achieve a serum concentration that includes the IC 50 of the particular compound being administered, as measured in an in vitro assay.
  • an initial dosage for humans may be based upon dosages found to be effective in animal models of the disease.
  • the initial dosage may be in the range of about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day, or about 1 mg/kg/day to about 50 mg/kg/day, or about 10 mg/kg/day to about 50 mg/kg/day, can also be used.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner.
  • compounds of the invention are for use in treatment which is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day, if desired.
  • the compounds of the invention and/or compositions thereof can be for use in combination therapy with at least one other therapeutic agent.
  • a compound of the invention and/or composition thereof and the therapeutic agent can act additively or, more preferably, synergistically.
  • the compounds of the invention can be for administration as the sole active pharmaceutical agent, they can also be for use in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are for administration at the same time or sequentially at different times, or the therapeutic agents can be for administration as a single composition.
  • Co-administration of a compound of the present invention and another pharmaceutical agent is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
  • Such combination products employ the compounds of this invention within the accepted dosage ranges.
  • Compounds of Formulae I, II, or III can also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of formula I may be for administration either prior to or after administration of the known anticancer or cytotoxic agent.
  • antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy.
  • Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • the compounds of the invention can be for co-administration with antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents.
  • Suitable antimetabolite antineoplastic agents can be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, camrabine, floxuridine, isopropyl pyrrolizine, methotrexate, uricytin, and the like
  • the compounds of the invention can be for co-administration with alkylating-type antineoplastic agents.
  • alkylating-type antineoplastic agents can be selected from but not limited to the group consisting of altretamine, anaxirone, bestrabucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, diplatinum cytostatic, elmustine, fotemustine, tauromustine, temozolomide, teroxirone, tetraplatin, trimelamol, and the like.
  • the compounds of the invention can be for co-administration with antibiotic-type antineoplastic agents.
  • Suitable antibiotic-type antineoplastic agents can be selected from but not limited to the group consisting of aclarubicin, actinomycin D, actinoplanone, anthracycline, bleomycin sulfate, bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, doxorubicin, doxorubicin-fibrinogen, erbstatin, esorubicin, glidobactin, herbimycin, idarubicin, illudins, oxalysine, oxaunomycin, sparsomycin, thrazine, zorubicin, and the like.
  • the compounds of the invention can be for co-administration with other antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of a-carotene, a-difluoromethyl-arginine, acitretin, amonafide, ankinomycin, antineoplaston A5, asparaginase, Avarol, bromofosfamide, caracemide, claviridenone, cytochalasin B, cytarabine, cytocytin, dacarbazine, paclitaxel, Efamol porphyrin, spirogermanium, taxol, thaliblastine, vinblastine sulfate, and the like.
  • antineoplastic agents including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consist
  • the invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and in vitro methods of using the inhibitors and inhibitor compositions.
  • the inhibitors and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases.
  • Also disclosed are methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.
  • the present compounds can also be for use in co-therapies with other anti-neoplastic agents, such as other kinase inhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), EGFR inhibitors such as Iressa, KDR inhibitors, COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD mimics or avß3 inhibitors.
  • other anti-neoplastic agents such as other kinase inhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP), EGFR inhibitors such as Iressa, KDR inhibitors, COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's, SOD
  • the compounds of the invention and/or compositions thereof may be for administration in combination with both ribovirin and an interferon.
  • the heterogeneous tan orange reaction mixture was cooled to room temperature.
  • the reaction mixture was diluted with EtOAc (75 mL).
  • Precipitated white solid formed was filtered.
  • the white solid was collected, treated with water, filtered and dried to provide N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1.75 g, 61%).
  • N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3-4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1 eq) prepared in Example 1 was dissolved in dry CH 2 Cl 2 (4.8 mL/mmol), alcohol (for carbamates) or thiol (for thiocarbamates) (2 eq), NEt 3 (7 eq) and DMAP (0.1 eq) were added successively under nitrogen atmosphere at room temperature. Contents were allowed to stir at room temperature and progress of the reaction mixture was monitored by LC/MS.
  • reaction mixture was concentrated upon consumption of carbamoylchloride.
  • the crude concentrate was treated with aq. NaHCO 3 and the resulting solid precipitated was filtered, washed with water, dried and purified by either silica gel column chromatography or preparative HPLC.
  • N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-[[2-(morpholin-4-yl)ethoxy]carbonyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine was prepared from 4-(2-hydroxyethyl)morpholine and N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine.
  • Trifluoracetic acid (0.04 mL, 59 mg, 0.519 mmol) was added to the stirring solution of 2S-N2-[[2-Amino-3-(1H-indol-3-yl)]propoxycarbonyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (93 mg, 0.118 mmol) in CH 2 Cl 2 (5 mL) at 0°C. Progress of the reaction was monitored by LC/MS. Reaction mixture was concentrated after 1hr of stirring the reaction mixture at 0°C.
  • N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- N2-[2-[4-(3-sulfopropyl)piperizin-1-yl]ethoxycarbonyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine was prepared in the similar manner as described in the general procedure from N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine and 4-(2-hydroxyethyl)-piperazinepropanesulfonic acid (EPPS) in CH 3 CN.
  • EPPS 4-(2-hydroxyethyl)-piperazinepropanesulfonic acid
  • N2-[2-(Dimethylamino)ethoxycarbonyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine was prepared from N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine and N,N-dimethylethanolamine.
  • the crude solid obtained was purified by preparative HPLC.
  • N2-[2-(Carboxymethyl)aminocarbonyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine was prepared in the similar as described in the general procedure from glycine and N2-chlorocarbonyl-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine.
  • the crude concentrated reaction mixture was treated with 1N aq.
  • reaction mixture was diluted with EtOAc (10 mL) at -78 °C. Reaction mixture was allowed to warm to room temperature while stirring. Solid precipitated from pale brown transparent reaction mixture after stirring the contents at room temperature for 1h. Reaction mixture was concentrated and diluted with water (15 mL). The precipitated solid was filtered and dried to provide (+/-)-N2-(1-chloroethoxycarbonyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (250 mg, 81%).
  • (+/-)-N2-(1-Chloroethoxycarbonyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 50 mg, 0.086 mmol
  • pyridine 34 mg, 0.43 mmol
  • NaI 129 mg, 0.86 mmol
  • the reaction mixture was concentrated, diluted with water (5 mL) and EtOAc (5 mL).
  • the remaining impurity was characterized as N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine.
  • Compounds were administered to rats orally at a dose of 4-5mg/kg using PEG-400 as a vehicle. Selected compounds were also administered as an IV bolus at a dose of 1 mg/kg.
  • Plasma samples were obtained from either the portal or jugular veins and analyzed by LC/MS/MS for both the parent pyrimidine-2,4-diamine and the prodrug compounds synthesized in the examples above. Bioavailability was calculated using the AUC of pyrimidine-2,4-diamine in jugular vein samples and the AUC of an IV bolus dose of pyrimidine-2,4-diamine.
  • Example 2 Rat and Human microsomes ⁇ 5 / ⁇ 5 Y Y Y
  • Example 3 Rat and Human microsomes ⁇ 5 / ⁇ 5 Y Y
  • Example 8 Rat and Human microsomes 35 / 10 Y Y 4
  • Half-life of prodrug in the presence of NASDPH 5 Determined by incubating compounds in microsomes in the absence of NADPH. All of the compounds in the list were stable in the absence of NADPH.
  • microsomes Studies were conducted in microsomes to determine whether the prodrug moieties could be hydrolyzed by CYP450 enzymes. The results from the use of compounds prepared in Examples 2, 3, and 8 provide clear evidence for P450 dependent cleavage of the prodrug moiety. Since microsomes lack many of the cytosolic enzymes present in rat and human liver, failure to detect pyrimidine-2,4-diamine in microsomal incubations does not preclude conversion in vivo.

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Claims (15)

  1. Verbindung der Formel (II)
    Figure imgb0030
    oder Salz davon, worin R3 Aryl oder Heteroaryl ist, jeweils optional substituiert;
    X3 und X4 unabhängig ausgewählt sind aus CH oder N;
    X5 ausgewählt ist aus der Gruppe, die besteht aus CR12R13, O, S, SO, SO2 und NR14, wobei R12 und R13 unabhängig ausgewählt sind aus H, OH, niederem Alkyl, oder zusammen eine Oxo-Gruppe bilden;
    R4 ausgewählt ist aus der Gruppe, die besteht aus -NO2, Halogen, -CN, Halogenalkyl, Alkoxy, Carboxylat und -OCF3;
    R5 und R6 unabhängig ausgewählt sind aus H, niederem Alkyl, Cycloalkyl oder Aryl;
    R14 H oder niederes Alkyl ist;
    X1 ausgewählt ist aus der Gruppe, die besteht aus O, S und NR11, wobei R11 H oder niederes Alkyl ist;
    X2 O oder S ist;
    R1 und R2 jeweils unabhängig ausgewählt sind aus der Gruppe, die besteht aus H, OH, -OR11, NR15R15, Halogen, niederem Alkyl, -C(O)O-Alkyl, -C(O)OH, -OP(=O)(OR11)2, -OC(=O)OR11, -OC(=O)R11, Cycloalkyl, Aryl und Heteroaryl, oder zusammen ein Oxo bilden, wobei R15 jeweils unabhängig ausgewählt ist aus der Gruppe, die besteht aus H, Alkyl, Prenyl, Allyl, -C(O)O-Alkyl, Cycloalkyl, Aryl, Heteroaryl, Alkaryl und Alkheteroaryl, oder sich zwei R15 verbinden, um ein optional substitutiertes Cycloheteroalkyl zu bilden;
    R ausgewählt ist aus der Gruppe, die besteht aus geradem oder verzweigtem, gesättigtem oder ungesättigtem Alkyl, Allyl, Cycloalkyl, Cycloheteroalkyl, Aryl, Heteroaryl, Prenylalkaryl und Heteroarylalkyl
    n eine ganze Zahl von 0 bis 10 ist;
    R7, R8, R9 und R10 unabhängig ausgewählt sind aus der Gruppe, die besteht aus H, Halogen, -OH, niederem Alkyl, Cycloalkyl, Aryl und Heteroaryl, oder wobei R7 und R8, oder R9 und R10 zusammen eine Oxo-Gruppe bilden,
    wobei
    Alkyl sich auf einen gesättigtem oder ungesättigten, verzweigten, geradkettigen oder cyclischen monovalenten C1- bis C15-Kohlenwasserstoff-Rest bezieht;
    niederes Alkyl sich auf ein C1- bis C6-Alkyl bezieht;
    Aryl sich auf ein monovalentes, aromatisches, ungesättigtes, cyclisches oder polycyclisches C6- bis C20-Ringsystem mit einem konjugierten n-Elektronensystem bezieht, wobei jeder Ring in einem kondensierten polycyclischen Aryl gesättigt oder ungesättigt ist mit der Maßgabe, dass mindestens ein Ring aromatisch ist;
    Heteroaryl sich auf einen 5- bis 20-gliedrigen monovalenten aromatischen Rest bezieht, in dem ein Kohlenstoff oder mehrere Kohlenstoffe unabhängig ersetzt sind durch dasselbe oder verschiedene Heteroatome, die ausgewählt sind aus N, P, O und S, wobei jeder Ring in einem kondensierten polycyclischen Heteroaryl gesättigt oder ungesättigt ist mit der Maßgabe, dass mindestens ein Ring aromatisch ist,
    und wobei
    optionale Substituenten an gesättigten Kohlenstoffatomen ausgewählt sind aus Ra, Halogen, -O-, =O, -ORb, -SRb, -S-, =S, _ -NRcRc, =NRb, =N-ORb, Trihalogenmethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Rb, -S(O)2O-, -(CH2)0-4S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, -OS(O)2ORb, -P(O)(O)2, -P(O)(ORb)(O-), -P(O)(ORb)(ORb), -C(O)Rb, -C(S)Rb, -C(NRb)Rb, -C(O)O-, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC(O)O--OC(O)ORb, -OC(S)ORb, -NRbC(O)Rb, -NRbC(S)Rb, -NRbC(O)O-, -NRbC(O)ORb, -NRbC(S)ORb, _NRbC(O)NRcRc, -NRbC(NRb)Rb und -NRbC(NRb)NRcRc, wobei
    optionale Substituenten an ungesättigten Kohlenstoffatomen ausgewählt sind aus Ra, Halogen, -O-, ORb, -SRb, -S-, _-NRcRc, Trihalogenmethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2Rb, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, -OS(O)zORb, -P(O)(O-)2, -P(O)(ORb)(O), -P(O)(ORb)(ORb), -C(O)Rb, -C(S)Rb, -C(NRb)Rb, -C(O)O-, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC(O)O-,-OC(O)ORb, -OC(S)ORb, -NRbC(O)Rb, -NRbC(S)Rb, -NRbC(O)O-, -NRbC(O)ORb, -NRbC(S)ORb, _NRbC(O)NRcRc, -NRbC(NRb)Rb und -NRbC(NRb)NRcRc,
    optionale Substituenten an Stickstoffatomen in Heteroalkyl- und Cycloheteroalkyl-Gruppen ausgewählt sind aus Ra, -O-, ORb, -SRb, -S-, _-NRcRc, Trihalogenmethyl, -CF3, -CN, -NO, -NO2, -S(O)2Rb, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, -OS(O)2ORb, -P(O)(O-)2, -P(O)(ORb)(O-), -P(O)(ORb)(ORb), -C(O)Rb, -C(S)Rb, -C(NRb)Rb, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC(O)ORb, -OC(S)ORb, -NRbC(O)Rb, -NRbC(S)Rb, -NRbC(O)ORb, -NRbC(S)ORb, -NRbC(O)NRcRc, -NRbC(NRb)Rb und -NRbC(NRb)NRcRc,
    Ra ausgewählt ist aus der Gruppe, die besteht aus Alkyl, Cycloalkyl, Heteroalkyl, Cycloheteroalkyl, Aryl, Arylalkyl, Heteroaryl und Heteroarylalkyl;
    Rb jeweils unabhängig Wasserstoff oder Ra ist; und
    Rc jeweils unabhängig Rb ist oder alternativ die zwei Rcs zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, ein 5-, 6- oder 7-gliedriges Cycloheteroalkyl bilden, das optional ein bis vier gleiche oder verschiedene zusätzliche Heteroatome enthalten kann,die ausgewählt sind aus der Gruppe, die besteht aus O, N und S.
  2. Verbindung oder Salz davon nach Anspruch 1, worin
    (a) X1 O ist, und optional X2 O ist; oder
    (b) R3 optional substituiertes Aryl ist, wobei das Aryl bevorzugt Alkoxyphenyl, Dialkoxyphenyl oder Trialkoxyphenyl ist, und das Trialkoxyphenyl optional Trimethoxyphenyl ist; oder
    (c) R4 H, OH, Halogen (optional F), Cyano, Nitro, Trifluormethyl, Difluormethyl, Fluormethyl, Trifluormethoxy, Difluormethoxy oder Fluormethoxy ist; oder
    (d) R5 und R6 H sind; oder
    (e) X4 CH oder N ist; oder
    (f) X5 CH2 oder O ist; oder
    (g) R7 und R8 H sind oder zusammen die Oxo-Gruppe bilden; oder
    (h) R9 und R10 Methyl sind; oder
    (i) R Cycloheteroalkyl ist, optional substituiertes oder unsubstituiertes Morpholin, oder substituiertes oder unsubstituiertes Pyrrolidin ist;
    oder Heteroaryl ist, optional substituiertes oder unsubstituiertes Indol, ist; oder ausgewählt ist aus Acetat, Amino, einem Dialkylamino; oder
    (j) n 1, 2 oder 3 ist.
  3. Verbindung oder Salz davon nach Anspruch 1, worin X1 NR11 ist und X2 optional O oder S ist; oder X1 S ist und X2 optional O ist.
  4. Verbindung nach Anspruch 1 der Formel (III):
    Figure imgb0031
    oder Salz davon, worin R ausgewählt ist aus der Gruppe, die besteht aus geradem oder verzweigtem, gesättigtem oder ungesättigtem Alkyl, Allyl, Cycloalkyl, Cycloheteroalkyl, Aryl und Heteroaryl;
    X1 O oder NR11 ist;
    R11 H oder niederes Alkyl ist; und
    n eine ganze Zahl zwischen 0 und 10 ist.
  5. Verbindung nach Anspruch 4, worin R ausgewählt ist aus Morpholin, 1-Methylpiperidin, Piperazin, 3-Piperazinpropan-sulfonat, Dimethylamin, Tryptamin oder N-tert-Butylacetyltryptamin.
  6. Verbindung nach Anspruch 4, worin n 0, 1, 2 oder 3 ist.
  7. In vitro-Verfahren zur Hemmung einer Kinase, wobei das Verfahren ein Kontaktieren der Kinase mit einer Verbindung oder einem Salz davon nach einem der Ansprüche 1 bis 6 aufweist, wobei die Kinase optional eine Tyrosin-Kinase ist, bevorzugt Syk-Kinase.
  8. Verfahren nach Anspruch 7, wobei die Verbindung oder das Salz davon Formel (II) entspricht
    Figure imgb0032
    worin X1 ausgewählt ist aus der Gruppe, die besteht aus O, S und NR11, wobei R11 H oder niederes Alkyl ist;
    X2 O oder S ist;
    X3 und X4 unabhängig ausgewählt sind aus CH oder N;
    X5 ausgewählt ist aus der Gruppe, die besteht aus CR12R13, O, S, SO, SO2 und NR14, wobei R12 und R13 unabhängig ausgewählt sind aus H, OH, niederem Alkyl, zusammen eine Oxo-Gruppe bilden, und R14 H oder niederes Alkyl ist;
    R ausgewählt ist aus der Gruppe, die besteht aus geradem oder verzweigtem, gesättigtem oder ungesättigtem Alkyl, Allyl, Cycloalkyl, Cycloheteroalkyl, Aryl, Heteroaryl, Prenylalkaryl und Heteroarylalkyl;
    R1 und R2 jeweils unabhängig ausgewählt sind aus der Gruppe, die besteht aus H, OH, -OR11, NR15R15, Halogen, niederem Alkyl, -C(O)O-Alkyl, -C(O)OH, -OP(=O)(OR11)2, -OC(=O)OR11, -OC(=O)R11, Cycloalkyl, Aryl und Heteroaryl, oder zusammen ein Oxo bilden, wobei R15 jeweils unabhängig ausgewählt ist aus der Gruppe, die besteht aus H, niederem Alkyl, Prenyl, Allyl, -C(O)O-Alkyl, Cycloalkyl, Aryl, Heteroaryl, Alkaryl und Alkheteroaryl, oder sich zwei R15 verbinden, um ein optional substituiertes Cycloheteroalkyl zu bilden;
    R3 Aryl oder Heteroaryl ist, jeweils optional substituiert;
    R5 und R6 unabhängig ausgewählt sind aus H, niederem Alkyl, Cycloalkyl oder Aryl;
    R7, R8, R9 und R10 unabhängig ausgewählt sind aus der Gruppe, die besteht aus H, OH, Halogen, niederem Alkyl, Cycloalkyl, Aryl und Heteroaryl, oder wobei R7 und R8 oder R9 und R10 zusammen eine Oxo-Gruppe bilden; und
    n eine ganze Zahl von 0 bis 10 ist.
  9. Verfahren nach Anspruch 8, wobei die Verbindung einer der folgenden Formeln
    Figure imgb0033
    Figure imgb0034
    Figure imgb0035
    Figure imgb0036
    Figure imgb0037
    Figure imgb0038
     oder
    Figure imgb0039
     und Salzen irgendeiner davon entspricht.
  10. Verbindung oder Salz davon nach einem der Ansprüche 1 bis 6 zur Verwendung in einem Verfahren zur Verhütung oder Behandlung von Neoplasie.
  11. Verbindung oder Salz davon zur Verwendung nach Anspruch 10, wobei die Verbindung wie in Anspruch 8 oder 9 definiert ist.
  12. Verbindung oder Salz davon nach einem der Ansprüche 1 bis 6, oder ein annehmbares Salz, N-Oxid, Hydrat oder Solvat davon zur Verwendung in einem Verfahren zur Verhütung oder Behandlung von Neoplasie, wobei die Verbindung oder das annehmbare Salz, N-Oxid, Hydrat oder Solvat davon dem Individuum in einer pharmazeutisch annehmbaren Trägersubstanz oder einem pharmazeutisch annehmbaren Verdünnungsmittel verabreicht wird.
  13. Verbindung oder Salz davon zur Verwendung nach Anspruch 12, wobei die Neoplasie Krebs ist.
  14. Verbindung oder Salz davon zur Verwendung nach Anspruch 13, wobei der Krebs Brustkrebs, Kolonkrebs, Lungenkrebs, Prostatakrebs oder ein hämopoetischer Tumor lymphoider Abstammung ist.
  15. Verbindung oder Salz davon zur Verwendung nach Anspruch 12, wobei das Individuum ein Haustier oder ein Mensch ist.
EP06851988.3A 2005-12-06 2006-12-06 Pyrimidin-2,4-diamine und ihre anwendungen Not-in-force EP1968598B1 (de)

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JP5207386B2 (ja) 2013-06-12
US20070129360A1 (en) 2007-06-07
US20070129362A1 (en) 2007-06-07
WO2008088303A1 (en) 2008-07-24
US7713987B2 (en) 2010-05-11
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EP1968598A4 (de) 2010-09-01
EP1968598A1 (de) 2008-09-17

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